Methylenebisphosphonic acid derivatives

ABSTRACT

The invention relates to novel methylenebisphosphonic acid ester amide derivatives of general formula (I), in which formula W 1 , W 2 , W 3  and W 4  are independently the group OR 1  or the group NR 2  R 3  wherein R 1 , R 2  and R 3  independently are hydrogen or straight or branched, optionally unsaturated C 1  -C 22  -alkyl, optionally substituted, optionally unsaturated C 3  -C 10  -cycloalkyl, aryl, aralkyl or silyl SiR 3 , or the groups R 2  and R 3  form together with the adjacent nitrogen atom a 3 to 10-membered saturated, partly saturated or aromatic heterocyclic ring, wherein in addition to the nitrogen atom, there may be one or two heteroatoms from the group N, O and S, provided that in formula (I) at least one of the groups W 1 , W 2 , W 3  and W 4  is hydroxy and at least one of the groups W 1 , W 2 , W 3  and W 4  is amino group NR 2  R 3 , Q 1  and Q 2  are independently hydrogen, fluorine, chlorine, bromine or iodine, including the stereoisomers, such as the geometrical isomers and the optically active isomers, of the compounds, as well as the pharmacologically acceptable salts of the compounds.

This is a 35 U.S.C. of PCT/FI91/00396, filed Dec. 18, 1991, nowWO92/11268.

This invention concerns novel methylenebisphosphonic acid derivatives,in particular novel halogen substituted methylenebisphosphonic acidamides and ester amides, processes for the preparation of these novelcompounds, as well as pharmaceutical compositions comprising these novelcompounds.

Several publications disclose methylenebisphosphonic acids, their saltsand some tetraesters, but there are only a few disclosures ofcorresponding partial esters, partial amides and partial ester amides.

The preparation of tetraesters of methylenebisphosphonic acids has beendescribed in the publications: J. Am. Chem. Soc. 78, (1956) 4450; J.Chem. Soc. (1959) 2272; J. Chem. Soc. 84 (1962) 1876; J. Org. Chem. 35,(1970) 3149; J. Org. Chem. 36, (1971.) 3843 and Phosphorus, Sulfur andSilicon 42, (1989) 73.

In the EP-patent application 356 866 optionally halogen substitutedmethylenebisphosphonic acid esters and amide esters are described, whichhave a cholesterol biosynthesis inhibiting activity.

According to the invention it has been discovered that the novel partialamides and partial ester amides of methylenebisphosphonic acids andtheir salts in many cases exhibit more favourable properties than thecorresponding bisphosphonic acids and salts due to their better kineticsand availability, their ability to participate as complex formers in theregulation of the metabolism of the organism being maintained.

They are well suited for the treatment of disorders relating to themetabolism of calcium and of other, especially bivalent metals. They maybe used both for the treatment of diseases in the skeletal system,especially of bone formation and resorption disorders, such as ofosteoporosis and. Paget's disease, as well as for the treatment ofdiseases in the soft tissues, such as of deposition and mineralisationconditions and bone formation disorders.

On the other hand, being pyrophosphate analogs, the new substitutedmethylenebisphosphonic acid derivatives are also suitable for thetreatment of disorders in the (pyro)phosphate functions of the organism,including those functions, wherein an active, but disturbance-prone orwrongly functioning organic part is coupled to (pyro)phosphate or actsas a metal complex or a combination of the last mentioned.

The novel bisphosphonates regulate either directly or over an indirectmechanism the quality and level of cations and/or pyrophosphatecompounds .freely present in the body fluids as well as of that bindingto, active in and liberated from the tissues. Thus they are able toregulate the cellular metabolism, growth and destruction. Consequentlythey are useful for the treatment of e.g. cancer of the bone andmetastases thereof, ectopic calcifications, urolithiasis, rheumatoidarthritis, bone infections and bone degradation.

Typical for the novel substituted methylenebisphosphonates is aselective desired and controlled action, providing for a bettertherapeutic index.

The invention concerns novel methylenebisphosphonic acid derivatives ofthe general formula I ##STR1## in which formula W¹, W², W³ and W⁴ areindependently the group OR¹ or the group NR² R³ wherein R¹, R² and R³independently are hydrogen or straight or branched, optionallyunsaturated C₁ -C₂₂ -alkyl, optionally substituted, optionallyunsaturated C₃ -C₁₀ -cycloalkyl, aryl, aralkyl or silyl SiR₃, or thegroups R² and R³ form together with the adjacent nitrogen atom a 3 to10-membered saturated, partly saturated or aromatic heterocyclic ring,wherein in addition to the nitrogen atom, there may be one or twoheteroatoms from the group N, O and S, provided that in the formula I atleast one of the groups W¹, W², W³ and W⁴ is hydroxy and at least one ofthe groups W¹, W², W³ and W⁴ is the amino group NR² R³ ,

Q¹ and Q² are independently hydrogen, fluorine, chlorine, bromine oriodine, including the stereoisomers, such as the geometrical isomers andthe optically active isomers, of the compounds, as well as thepharmacologically acceptable salts of the compounds.

Alkyl, alkenyl and alkynyl as the group R¹, R² and R³ containindependently 1 to 22, respectively 2 to 22 carbon atoms, preferably 1to 7, respectively 2 to 7, and advantageously 1 to 4, respectively 2 to4 carbon atoms.

Cycloalkyl or -alkenyl as the group R¹, R², and R³ contains 3 to 10C-atoms, preferably 5 or 6 carbon atoms, and it may-unsubstituted orsubstituted for example with lower (1-4C) alkyl. Advantageously it iscyclopropyl, -butyl, -pentyl, -hexyl or -heptyl or the correspondingcycloalkenyl group.

Aryl or aralkyl as the group R¹, R² and R³ means optionally C₁ -C₄-lower alkyl, -lower alkoxy or halogen substituted monocyclic aryl oraralkyl, such as phenyl and benzyl, preferably, however, unsubstitutedphenyl or benzyl. Halogen is chlorine, bromine, fluorine or iodine.

In the silyl group SiR₃ the group R³ is lower alkyl containing 1 to 4C-atoms, and is especially methyl, ethyl, isopropyt, butyl, t-butyl, orit is phenyl or R³ -substituted ted phenyl, whereby also differentcombinations of lower alkyls and phenyls come into question, such asdimethyl t-butyl, methyl diisopropyl, dimethyl phenyl, diethyl phenyl,methyl t-butyl phenyl, diisopropyl-(2,6-dimethyl phenyl).

When R² and R³ together with the nitrogen atom form a heterocyclic,either saturated ring, this is typically for example morpholinyl,thiomorpholinyl, piperidinyl, piperazinyl, azetidinyl, aziridinyl,pyrrolidinyl, or a partly hydrogenated aromatic ring it is for examplepyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, azepinyl. This group can besubstituted as has been mentioned earlier for cycloalkyl, but it ispreferably, however, unsubstituted, such as pyrrolidinyl, morpholinyl orpiperazinyl.

Q¹ and Q² are both preferably chlorine.

Salts of the compounds of the formula I are especially their salts withpharmaceutically acceptable bases, such as metal salts, for exampleAlkalimetal salts, especially litium, sodium and potassium salts,alkaline earth metal salts, such as calcium or magnesium salts, copper,aluminium or zinc salts, as well as ammonium salts with ammonia or withprimary, secondary and tertiary, both aliphatic and alicyclic as well asaromatic amines, and quaternary ammonium salts, such as halides,sulphates and hydroxides, salts with aminoalcohols, such as ethanol-,diethanol- and triethanolamines, tris(hydroxymethyl)aminomethane, 1- and2-methyl- and 1,1-, 1,2- and 2,2-dimethylaminoethanols, N-mono- andN,N-dialkylaminoethanols, N-(hydroxymethyl- andethyl)-N,N-ethanediamines, as well as amino crown ethers and cryptates,and heterocyclic ammonium salts, such as azetidinium, pyrrolidinium,piperidinium, piperazinium, morpholinium, pyrrolium, imidazolium,pyridinium, pyrimidinium, quinolinium, etc., salts.

Examples of preferred compounds of the invention are:

(Dichloromethylene) bisphosphonic acid P, P, P'-tris (diethyl amide)

(dichloromethylene) bisphosphonic acid P-monoisopropyl ester P-mono(diethylamide),

(dichloromethylene) bisphosphonic acid P,P-bis(diethylamide)

(dichloromethylene)bisphosphonic acid mono(diethylamide)

(dichloromethylene) bisphosphonic acid mono(phenyl-N-methyl amide)

(dichloromethylene)bisphosphonic acid mono(benzylamide)

(dichloromethylene) bisphosphonic acid P, P'-bis (diethylamide).

The invention concerns also a process for the preparation of thecompounds of the formula I, according to which

a) in a compound of the formula ##STR2## in which formula

Q¹ and Q² have the same meaning as above and W¹, W², W³ and W⁴ have thesame meaning as above, except hydroxy, at least one ester group OR¹and/or amino group NR² R³ is hydrolysed to a free hydroxy group, inorder to prepare a partial amide or partial ester amide derivative ofthe formula I, or

b) in a methylenebisphosphonic acid tetraacid or its partial ester ofthe formula ##STR3## which optionally is in acid chloride form, andwherein Q¹ and Q² have the same meaning as above, the groups W^(I) to W⁴mean the group OR¹, wherein at least one of the groups R¹ is hydrogen,and the remaining groups R¹ have the same meaning as above, when in thecompound I" there is one hydroxy group, at least one ester group OR¹ isconverted to an amide group, and when in the compound I" there are morethan one hydroxy group, a free hydroxy group is amidated with a suitableamine NHR² R³ and/or an ester group is converted to an amide group inorder to prepare a partial amide or partial ester amide of the formulaI, having at least one hydroxy group and at least one amine group, or

c) a phosphonate having the formula ##STR4## is reacted with anactivated phosphate or a hydrogen phosphonate corresponding to theformula X ##STR5## wherein in the formulas; Y is hydrogen, hydroxy orhalogen or other leaving group, Z is hydrogen, halogen, acyloxy,sulphonyloxy, alkoxy or aryloxy, and W¹ to W⁴ and Q¹ and Q² have thesame meaning as above, or is reacted with a phosphite corresponding tothe formula X, or

d) a bisphosphonite compound having the formula ##STR6## wherein W¹ toW⁴ and Q¹ and Q² have the same meaning as above, or the correspondinghydrogen phosphonate compound, is oxidized to a compound of the formulaI, and/or if desired, a compound of the formula I obtained, wherein Q¹and/or Q² are hydrogen, is converted to a compound of the formula I,wherein Q¹ and/or Q² are halogen, and/or a compound of the formula Iobtained, wherein Q¹ and/or Q² are halogen, is mono- or di-dehalogenatedto a compound of the formula I, wherein Q¹ and/or Q² are hydrogen,and/or, if desired, a compound of the formula I obtained is converted toanother compound according to the formula I by esterification,transesterification, amidation or transamidation and/or, if desired, apartial amide or partial ester amide acid obtained is converted to asalt or an obtained salt is converted to the free acid.

Thus according to one process the compounds are prepared by selectivehydrolysis of the ester or amide groups of the tetra(amideester)compounds corresponding to the formula I. Thus a compound is usedas the starting material, wherein Q¹ and Q² have the same meaning asabove and the groups W¹ to W⁴ have the same meaning as in the formula I,except hydroxy, and at least one of the groups W¹ to W⁴ is the aminogroup NR² R³ and of the ester or amide groups contained in the compoundat least one is hydrolyzed to the free hydroxy group, or several so thatat least one amide group remains.

The progress of hydrolysis may be followed for examplechromatographically or by using ³¹ P-NMR-spectroscopy. The reaction maybe interrupted when the concentration of a desired partial (ester) amideis at its greatest and the product may be isolated from the reactionmixture either as the free acid or a salt by precipitation, extractionor chromatographically, and a salt form may be converted into the freeacid -or a free acid may be converted into its salt.

The compounds according to this invention may also be prepared byselective esterification and amidation of bisphosphonic acids. Atetraacid (W¹ to W⁴ =OH) may thus used as a starting material, which canbe the free acid or a salt, such as a metal or ammonium salt, or thecorresponding bisphosphonic acid tetrachloride, and a suitable amineNHR² R³. Similarly, a suitable partial ester acid, partial amide acid orpartial ester amide acid or a salt thereof or the corresponding acidchloride may be used. The ester group may be exchanged to an amide groupover the acid halide or directly using known methods.

Partial amides and ester amides according to the invention may also beprepared by constructing the P-C-P frame from its parts ##STR7## whereinin the formula Y is hydrogen, hydroxy or halogen or other leaving group,Z is halogen, acyloxy, sulphonyloxy, alkoxy or aryloxy, and W¹ to W⁴ andQ¹ and Q² have the meaning given above. As the base, for example, sodiumhydride, butyl litium or litium diisopropylamide may be used. In thestarting material optionally present free acid sites and/or aminehydrogens (one of the groups R¹ to R³ =H) have to be neutralized, byusing a sufficient amount of base, prior to the coupling reaction.

Also the Michaelis-Arbuzov reaction may be used, whereby the secondreacting compound is a phosphite, or the Michaelis-Becker reaction,whereby Z is hydrogen.

The amides and ester amides according to the invention may also beprepared from P-C-P-structures at a lower oxidation level by oxidation##STR8## whereby in the formulas W¹ to W⁴ and Q¹ and Q² have the meaninggiven above, and whereby the phosphonite structure may exist in anequilibrium with the hydrogenphosphonate structure. All conventionaloxidation agents, or their solutions, such as hydrogen peroxide,perhalogen compounds, peracids, permanganate etc., come into question asoxidating agents.

The compounds according to the invention may also be prepared byhalogenating corresponding compounds, wherein one or both of the groupsQ¹ and Q² are hydrogen, or exchange the halogen(s) for another, orremove one or both: ##STR9##

In the formulas W¹ to W⁴ and Q¹ and Q² are the same as before.Halogenation takes place as is described later.

Partial amides and ester amides of bisphosphonic acids according to theinvention may also be prepared from other partial amides or ester amidesby performing an intra- or intermolecular exchange reaction.

The tetra(ester)amides and corresponding tetraacids used as startingmaterials in the above reactions may be prepared by processes known assuch from literature by constructing the P-C-P frame from its parts, forexample using the above mentioned Michaelis-Becker-, Michaelis- Arbuzov-or carbanion reaction.

The compounds prepared may, if necessary, be converted into othersuitable compounds by using exchange reactions taking into account thepreparation of a desired partial (ester)amide. Thereby the amide groupsand ester groups W¹ to W⁴ may be converted directly or over thecorresponding phosphonochloride or by using other known methods.

Halogen atoms(s) may be introduced in place of the hydrogens on thecarbon between the phosphorus atoms of the bisphosphonates also in theform of tetra(ester)amides, whereby the reaction advantageously takesplace with hypohalite. Also conventional halogenation reactions comeinto question, such as the reactions of bisphosphonic carbanionsprepared with a strong base with elemental halogens or halogenationswith N-haloamines and other active halides or polyhalogen compounds.

The halogen substituents of the carbon may also be introduced in thebisphosphonate structure as a halogenated monophosphonate IX, whereby Q¹and/or Q² are halogens. A halogen in a carbon of the frame may also beexchanged to hydrogen, often by nucleophilic dehalogenation, or toanother halogen using known reactions. Mixed halogen compounds may alsobe prepared applying the above mentioned halogenation and exchangereactions stepwise (cf Phosphorus and Sulfur, 37 (1988) 1).

Optically active partial amides and partial ester amides may be preparedbest by using known optically active compounds, such as optically activealcohols, in the preparation of the above mentioned starting materials,intermediates and end products, or in the exchange reactions.

The properties of the compounds according to the invention have beentested in the following test system.

The parathyroid hormone stimulated bone resorption inhibition activityof the compounds in vitro in mouse calvaria was determined (Reynolds &Dingle (Calc Tiss Res 1970; 4:339).

                  TABLE 2                                                         ______________________________________                                        Antiresorptive activity                                                       Inhibition of resorption (%)                                                                          100 μM                                             ______________________________________                                        Clodronate                43                                                  (dichloromethylene)bisphosphonic acid                                         mono(diethylamide)        43                                                  (dichloromethylene)bisphosphonic acid                                         P,P'-bis(diethylamide)    38                                                  (dichloromethylene)bisphosphonic acid                                         tris(diethylamide)        44                                                  (dichloromethylene)bisphosphonic acid                                         P-monoisopropyl ester P-mono(diethylamide)                                                              44                                                  ______________________________________                                    

From the table the superior relative in vitro activity of the compoundsof the invention are evident when taking into account that they bindonly to a limited degree to hydroxyapatite and partly inhibit crystalgrowth. They provide for a better therapeutic index, exhibiting lesserside effects.

The partial amides and partial ester amides of substituted bisphosphonicacids of the formula I may be used as pharmaceuticals as such, or astheir pharmacologically suitable salts, such as the alkali or ammoniumsalts. Such salts may be prepared by reacting the (ester)amide acidswith the corresponding inorganic or organic bases. Depending on thereaction conditions, the amide or ester amide salts may also be formeddirectly in the above mentioned reactions.

The new compounds I according to this invention may be administeredenterally or parenterally. All conventional administration forms, suchas tablets, capsules, granules, syrups, solutions, implants andsuspensions come into question. Also all adjuvants for manufacture,dissolution and administration of the preparation, as well asstabilizers, viscosity regulating and dispersion agents and buffers, maybe used.

Such adjuvants include i.a. tartrate and citrate buffers, alcohols, EDTAand other nontoxic complexing agents, solid and liquid polymers andother sterile substrates, starch, lactose, mannite, methylcellulose,talc, silicic acids, fatty acids, gelatine, agar-agar, calciumphosphate, magnesium stearate, animal, and vegetable fats and, ifdesired, flavouring and sweetening agents.

The dosage depends on several factors, for example on the manner ofadministration, species, age and individual condition. The daily dosesare about 1 to 1000 mg, usually 10 to 200 mg per person, and they may beadministered as a single dose or may be divided into several doses.

In the following, examples of a typical capsule and a tablet are given:

    ______________________________________                                                              mg/caps.                                                ______________________________________                                        Capsule                                                                       Active ingredient       100.0 mg                                              Starch                  20.0 mg                                               Magnesium stearate      1.0 mg                                                Tablet                                                                        Active ingredient       400.0 mg                                              Microcrystalline cellulose                                                                            20.0 mg                                               Lactose                 67.0 mg                                               Starch                  10.0 mg                                               Talc                    4.0 mg                                                Magnesium stearate      1.0 mg                                                ______________________________________                                    

For medicinal use, also an intramuscularly or parenterally administeredpreparation may be made, for example an infusion concentrate, wherein asadjuvants e.g. sterile water, phosphate buffer, NaCl, NaOH or HCl orother known pharmaceutical adjuvants suitable for the purpose may beused.

The compounds in amide and ester amide acid form according to theinvention are liquid or waxy substances, usually soluble in organicsolvents and in some instances in water. Their salts are solid,crystalline or typically powdery substances which-usually dissolve wellin water, in some instances in organic solvents, but only some structuretypes being poorly soluble in all solvents. The compounds are verystable, also in their neutral solutions at room temperature.

The structure of the compounds may easily be verified with ¹ H-, ¹³ C-and ³¹ P-NMR-spectroscopy and FAB-masspectrometry, or when silylated,with EI-masspectrometry. For concentration and impurity determinations31P-NMR-spectroscopy is very suitable. Also for polar compounds as suchion exchange and exclusion-HPLC may be used and for tetra(ester)amidesand corresponding silylated derivatives GLC or GC/MS may be used. Fromthe compounds nitrogen, sodium and other metals were determinedseparately as well as the possible crystal water content.

The following examples illustrate the invention without limiting thesame in any way.

EXAMPLE 1 (Dichloromethylene) bisphosphonic acid P', P'-bis(diethylamide) and its disodium salt

3.83 g (0.01 moles) of (dichloromethylene)bisphosphonic acidP,P-dimethyl ester P',P'-bis(diethylamide) is dissolved in 20 ml ofanhydrous methylene chloride and 3.06 g (0.02 moles) ofbromotrimethylsilane is added while stirring as well as 3.00 g (0.02moles) of sodium iodide and the mixture is stirred for 6 hours at roomtemperature (the progress of the reaction is followed by NMR). Thesolvent is evaporated) in vacuum and the residue dissolved in anhydrousether. The mixture is filtered and the filtrate is evaporated toconstant weight under vacuum, whereby (dichloromethylene)bisphosphonicacid P,P-bis(trimethylsilyl ester) P',P'-bis(diethylamide) is obtainedin a quantitaive yield as a brown oil. The evaporation residue isdissolved in 30 ml of methanol and the solution stirred for 5 min atroom temperature and evaporated to a constant weight under vacuum,whereby (dichloromethylene)bisphosphonic acid P',P'-bis(diethylamide) isobtained as a brown, thick-flowing oil. This is dissolved in 35 ml ofmethanol-acetone (1:1) and to the solution 3 ml of a 5N NaOH solution isadded while stirring and cooling. The solution is evaporated undervacuum and to the residue acetone is added and the mixture is stirred.The precipitate is filtered and washed with acetone and air-dried. Yieldis appr. 2.8 g (70% of theor.) of colourless, crystalline(dichloromethylene)bisphosphonic acid P',P'-bis(diethyl amide) disodiumsalt (³¹ P-NMR (D₂ O): δ8.60 ppm (P), 32.16 ppm (P'), ² J_(PP) =15.6 Hz,³ J_(PH) =9.2 Hz), the concentration of which is >90%.

I.a. the following bisphosphonic acid amides and ester amides as well astheir sodium salts may be prepared in an analogous manner:

From P'-ethyl P-methyl P,P'-bis(diethylamido) (dichloromethylene)bisphosphonate over P,P'-bis(trimethylsilyl) P,P'bis (diethylamido)(dichloromethylene)bisphosphonate:

P,P'-bis(diethylamido) (dichloromethylene) bisphosphonate (cf. Example6) (³¹ P-NMR (CDCl₃): δ15.66 ppm) which can be converted to its disodiumsalt as has been described above (³¹ P-NMR (D₂ O): δ13.94 ppm).

From P'-ethyl P,P-dimethylP'-morpholino(dichloromethylene)bisphosphonate (see Example 4) overP,P,P'-tris(trimethylsilyl)P'-morpholino(dichloromethylene)bisphosphonate:

P'-morpholino (dichloromethylene)bisphosphonate (³¹ P-NMR (D₂ O): δ6.02(P), 18.06 (P'), ² J_(PP) 17.6 Hz) and trisodium salt (³¹ P-NMR (D₂ O):δ9.44 ppm (P), 10.75 ppm (P'), ² J_(PP) =18.1 Hz).

From P,P,P'-trimethyl P'-dibutylamido (dichloromethylene)bisphosphonate(see Example 4) over P,P,P'-tris (trimethylsilyl) P'- (dibutylamido)(dichloromethylene) bisphosphonate:

P'- (dibutylamido) (dichloromethylene) bisphosphonate (trisodium salt,³¹ P-NMR (D₂ O): δ9.58 ppm (P), 12.58 ppm (P'), ² J_(PP) =15.2 Hz).

From P-methyl P'-butylamido(dichloromethylene) bisphosphonate (seeExample 6) (or P,P,P'-trimethyl P'-(butylamido)(dichloromethylene)bisphosphonate) over P,P,P'-tris(trimethylsilyl)P'-(butylamido) (dichloromethylene) bisphosphonate:

P'-(butylamido) (dichloromethylene) bisphosphonate (³¹ P-NMR (D₂ O):δ7.11 ppm (P), 9.49 ppm (P'), ² J_(PP) =21.0 Hz).

From P-ethyl P,P'-dimethyl P'-(dioctylamido)(dichloromethylene)bisphosphonate (see Example 4) overP,P,P'-tris(trimethylsilyl) P'- (dioctylamido)(dichloromethylene)-bisphosphonate (³¹ P-NMR (CDCl₃): δ-7.16 ppm (P),6.28 pm (P'), ² J_(PP) =27.2 Hz):

P'-(dioctylamido) (dichloromethylene) bisphosphonate (³¹ P-NMR (CDCl₃):δ9.78 ppm (P), 15.41 ppm (P') ² J_(PP) =23.2 Hz) and trisodium salt (³¹P-NMR (D₂ O): δ12.23 ppm (P), 18.01 ppm (P') ² J_(PP) =22.0 Hz).

From P'-ethyl P,P-dimethyl P'-(benzylmethylamido)(dichloromethylene)bisphosphonate (see Example 4 ) over P,P,P'-tris(trimethylsilyl)P'-(benzylmethylamido) (dichloromethylene)bisphosphonate:

P'-(benzylmethylamido) (dichloromethylene) bisphosphonate (³¹ P-NMR (D₂O): δ10.32 ppm (P), 15.60 ppm (P'), ² J_(PP) =14.9 Hz).

From P'-ethyl P,P-dimethylP'-(benzylmethylamido)(chloromethylene)bisphosphonate (see Example 10)over P,P,P'-tris(trimethylsilyl)P'-(benzylmethylamido)(chloromethylene)bisphosphonate:

P'-(benzylmethylamido)(chloromethylene)bisphosphonate.

From P,P,P'-trimethyl P'-(diethylamido) (chloromethylene) bisphosphonate(see Example 10) over P,P,P'-tris(trimethylsilyl) P'-(diethylamido)(chloromethylene) bisphosphonate:

P'-(diethylamido) (chloromethylene) bisphosphonate (trisodium salt, ³¹P-NMR (D₂ O): δ9.61 ppm (P), 17.84 ppm (P'), ² J_(PP) =2.9 Hz).

From P,P-dimethyl P',P'-bis(diethylamido)(chloromethylene)bisphosphonate (see Example 10) overP,P-bis(trimethylsilyl) P', P'-bis (diethylamido) (chloromethylene)bisphosphonate:

P', P'-bis (diethylamido) (chloromethylene) bisphosphonate (disodiumsalt; ³¹ P-NMR (D₂ O): δ7.94 ppm (P), 34.17 ppm (P'), ² J_(PP) =3.1 Hz,² _(PP) =16.7 Hz) P,P-dimethylP',P'-bis(diethylamido)(dichloromethylene)bisphosphonate used as thestarting material above may be prepared in the following manner:

Step 1

Into a THF-hexane solution of LDA (litium diisopropylamide), whichcontains 0.10 moles of LDA, 10.31 g (0.05 moles) of methyl phosphonicacid bis (diethylamide) (³¹ P-NMR (CDCl₃): δ34.63 ppm) (prepared frommethane phosphonic acid dichloride and diethyl amine) in 20 ml anhydrousTHF is added while stirring under a N₂ -atmosphere at -75° -78° C. Afterthe addition,, the mixture is stirred for 15 min, whereafter 7.22 g(0.05 moles) of chlorophosphonic acid dimethyl ester is added in 10 mlof anhydrous THF and stirring is continued for an additional 15 min at-75°--78° C. The temperature of the mixture is raised to about -50° C.and pH is adjusted to about 5-6 with 5N HCl. The mixture is heated toroom temperature and the solvents are distilled under vacuum. Theresidue is extracted with 3×70 ml of CHCl₃ and the combined extracts arewashed with a 10% NaHCO₃ -solution and water and is dried (MgSO₄) andfiltered. The filtrate is evaporated under vacuum, whereby appr. 15.7 g(100% of theor) of P,P-dipethylP',P'-bis(diethylamido)methylenebisphosphonate is obtained as a lightyellow oil (³¹ P-NMR (CDCl₃): δ25.43 ppm (P), 25.51 ppm (P'), ² J_(PP)=4.5 Hz), the concentration of which is 98%.

I.a. the following symmetrical and unsymmetrical methylenebisphosphonicacid ester amides can be prepared in an analogous manner:

From methyl(diethylamido)methylphosphonate (³¹ P-NMR (CDCl₃): δ34.56ppm) and dimethylchlorophosphonate P,P,P'-trimethyl P'-(diethylamido)methylenebisphosphonate (³¹ P-NMR (CDCl₃): δ23.89 ppm (P.) 25.11 ppm(P'), ² J_(PP) =5.4 Hz).

From methyl (diethylamido) methylphosphonate and ethyl(diethylamido)chlorophosphonate (³¹ P-NMR (CDCl₃): δ16.51 ppm) P'-ethylP-methyl P,P'-bis (diethylamido) methylenebisphosphonate (³¹ P-NMR(CDCl₃): δ26.69/26.66 ppm (P'), 24.78/24.91 ppm (P), ² J_(PP) =7.7/1.9Hz).

From isopropyl (diethylamido) methylphosphonate (³¹ P-NMR (CDCl₃):δ27.67 ppm) and dimethylchlorophosphonate P,P-dimethyl P'-isopropylP'-(diethylamido) methylenebisphosphonate (³¹ P-NMR (CDCl₃): δ22.10 ppm(P), 24.38 ppm (P'), ² J_(PP) =5.8 Hz).

From dimethylmethylphosphonate and ethylmorpholinochlorophosphonate (³¹P-NMR (CDCl₃): δ14.16 ppm) P'-ethyl P,P-dimethylP'-morpholinomethyienebisphosphonate (³¹ P-NMR (CDCl₃): δ21.43 ppm (P),23.39 ppm (P'), ² J_(PP) =3.4 Hz)

From methyl (dibutylamido) methylphosphonate (³¹ P-NMR (-CDCl₃): δ35.94ppm) and dimethylchlorophosphonate P,P,P'-trimethyl P'-(dibutylamido)methylenebisphosphonate (³¹ P-NMR (CDCl₃): δ24.11 ppm (P), 25.30 ppm(P') ² J_(PP) =6.1 Hz).

From dimethylmethylphosphonate and ethyl (dioctylamido)chlorophosphonate (³¹ P-NMR (CDCl₃): δ17.23 ppm) P'-ethyl P,P-dimethylP'-(dioctylamido) methylenebisphosphonate (³¹ P-NMR (CDCl₃): δ23.70 ppm(P), 24.39 ppm (P'), ² J_(PP) =6.4 Hz).

From bis (diethylamido) methylphosphonate (³¹ P-NMR (CDCl₃): δ34.63 ppm)and ethyl (diethylamido) chlorophosphonate (³¹ P-NMR (CDCl₃): δ16.51ppm) P-ethyl P,P'P'-tris(diethylamido)methylenebisphosphonate (³¹ P-NMR(CDCl₃): δ27.13 ppm (P), 27.35 ppm (P'), ² J_(PP) =3.9 Hz ).

From dimethylmethylphosphonate and ethyl(benzylmethylamido)chlorophosphonate (³¹ P-NMR (CDCl₃): δ17.69 ppm) P'-ethyl P,P-dimethylP'-(benzylmethylamido) methylenebisphosphonate (³¹ P-NMR (CDCl₃): δ24.19ppm (P), 24.29 ppm (P'), ² J_(PP) =3.0 Hz)

From diethylmethylphosphonate and ethylpiperidinochlorophosphonate (³¹P-NMR (CDCl₃): ) P,P,P'-triethyl P'-piperidinomethylenebisphosphonate.

From dimethylmethylphosphonate and methyl (diallylamido)chlorophosphonate (³¹ P-NMR (CDCl₃): δ16.18 ppm P,P,P'-trimethylP'-(diallylamido) methylenebisphosphonate.

From dimethylmethylphosphonate and ethyl(N-methylpiperazino)chlorophosphonate (³¹ P-NMR (CDCl₃): δ14.84 ) P'-ethyl P,P-dimethylP'-(N-methylpiperazino)methylenebisphosphonate (³¹ P-NMR (CDCl₃): δ21.72ppm (P), 23.92 ppm (P') ² J_(PP) =3.4 Hz).

Step 2

15.7 g (0.05 moles) of the evaporation residue of methylenebisphosphonicacid P,P-dimethyl ester P',P'-bis(diethylamide) obtained in Step 1 isdissolved in 200 ml of CCl₄ and 200 ml of a 10% NaOCl-solution and 10 gof benzyl triethyl ammonium chloride is added. The mixture is stirredfor 45 min at room temperature (the progress of the reaction is followedby NMR) and the organic phase is separated and washed with water anddried (Na₂ SO₄) and filtered. The filtrate is evaporated under vacuum,whereby appr. 15.3 g (80% of theor.) of (dichloromethylene)bisphosphonicacid P,P-dimethyl ester P',P'-bis(diethylamide) is obtained as a lightyellow oil (³¹ P-NMR (CDCl₃): δ12.91 ppm (P), 25.31 ppm (P'), ² J_(PP)=22.7 Hz) the concentration of which is 97%.

I.a. the following symmetrical and unsymmetrical(dichloromethylene)bisphosphonic acid ester amides can be prepared in ananalogous manner:

From P-ethyl P'-methyl P,P'-bis (diethylamido) methylenebisphosphonate:P-ethyl P'-methyl P,P'-bis(diethylamido) (dichloromethylene)bisphosphonate (³¹ P-NMR (CDCl₃): δ16.39/16.48 ppm (P), 18.60/18 36 ppm(P'), ² J_(PP) =20.5/17.9 Hz).

From P-ethyl P,P',P'-tris (diethylamido) methylenebisphosphonate:P-ethyl P,P', P'-tris (diethylamido) (dichloromethylene) bisphosphonate(³¹ P-NMR (CDCl₃): δ17.66 ppm (P), 26.54 ppm (P'), ² J_(PP) =20.7 Hz).

EXAMPLE 2 (Dichloromethylene) bisphosphonic acid tris (diethylamide) andits piperidinium salt

4.4 g (0.01 moles) of (dichloromethylene)bisphosphonic acid P-ethylester P,P',P'-tri(diethylamide) (see Example 1) is stirred in 22 ml ofpiperidine for 1 h at appr. 100° C. and the excess piperidine isevaporated under vacuum. The residue is stirred while cooling into 15 mlof anhydrous ether and the precipitate filtered and air-dried. Yield isappr. 4.2 g (85% of theor.) of colourless, crystalline(dichloromethylene) bisphosphonic acid tris (diethylamide) piperidiniumsalt (³¹ P-NMR (CDCl₃): δ12.26 ppm (P), 30.19 ppm (P'), ² J_(PP) =16.5Hz), the concentration of which is 99% and from which the correspondingacid can be liberated with acid treatment.

In the same manner (dichloromethylene)bisphosphonic acid tris(diethylamide)-(N-ethylpyridinium salt) (³¹ P-NMR (CDCl₃): δ10.23 ppm(P), 29.51 ppm (P'), ² J_(PP) =17.7 Hz) has been prepared using pyridinetreatment.

EXAMPLE 3 P'-Morpholino (dichloromethylene) bisphosphonic acid ethylester

1.85 g (0.005 moles) of P'-morpholino(dichloromethylene)bisphosphonicacid P'-ethyl P,P-dimethyl ester (see Example 4) and 1.84 g (0.012moles) of trimethylsilyl bromide in 30 ml of anhydrous CH₂ Cl₂ isstirred under reflux for 30 min and evaporated under vacuum. The residueis dissolved in 30 ml of anhydrous CH₃ OH and Stirred for 15 min at roomtemperature and evaporated under vacuum, whereby appr. 1.7 g (80% oftheor.) of P'-morpholino(dichloromethylene)bisphosphonic acid P'-ethylester is obtained (³¹ P-NMR (CDCl₃): δ8.29 ppm (P), 13.39 ppm (P'), ²J_(PP) =22.6 Hz) as a yellow oil at a concentration of >85%.

EXAMPLE 4 Dichloromethylene)bisphosphonic acid (mono)diethylamide andits trisodium salt

5.5 g (0.02 moles) of methylenebisphosphonic acid P,P,P'-trimethyl esterP'-diethylamide (see Example 1) is added at 0° C. while stirring to amixture containing 26 g NaHCO₃, 68 ml of a 10% NaOCl-solution and 30 gof ice, whereafter the mixture is stirred for 1.5 hours at 0° C. and 2.5hours at room temperature (the progress of the reaction is followed withNMR). The mixture is filtered and the filtrate extracted with toluene.The combined toluene extracts are washed with a 10% NaHCO₃ -solution anddried (Na₂ SO₃) and filtered. The filtrate is evaporated under vacuum,whereby appr., 5.8 g (85% of theor.) of (dichloromethylene)bisphosphonicacid P,P,P'-trimethyl ester P'-diethylamide is obtained (³¹ P-NMR(CDCl₃): δ12.02 ppm (P), 17.09 ppm (P'), 17.09 ppm (P'), ² J_(PP) =21.4Hz) as a colourless oil at a concentration of >97%.

The evaporation residue is hydrolysed to (dichloromethylene)bisphosphonic acid (mono) diethylamide (³¹ P-NMR (CDCl₃): δ10.00 ppm(P), 13.90 ppm (P'), ² J_(PP) =18.5 Hz) over (dichloromethylene)bisphosphonic acid P,P,P'-trimethylsilyl ester P'-diethylamide (³¹ P-NMR(CDCl₃): δ-9.10 ppm (P), 5.29 ppm (P'), ² J_(PP) =25.7 Hz ) in themanner described in the Example 1 at a yield of appr. 90%.

The product can be converted to the corresponding trisodium salt bytreating an acetone solution of the material with three equivalents of a5N NaOH-solution. The concentration of the trisodium salt crystallizedfrom water-methanol (³¹ P-NMR (D₂ O): δ10.23 ppm (P), 15.72 ppm (P'), ²J_(PP) =15.2 Hz) is >95%.

I.a. the following symmetrical and unsymmetrical(dichloromethylene)bisphosphonic acid ester amides can be prepared in ananalogous manner:

From P,P-dimethyl P'-isopropyl P'-(diethylamido) methylenebisphosphonate(see Example 1) P,P-dimethyl P'-isopropyl P'-(diethylamido)(dichloromethylene) bisphosphonate (³¹ P-NMR (CDCl₃): δ12.13 ppm (P),13.50 ppm (P') ² J_(PP) =22.8 Hz).

From P'-ethyl P,P-dimethyl P'-morpholinomethylenebisphosphonate (seeExample 1) P'-ethyl P,P-dimethylP'-morpholino(dichloromethylene)bisphosphonate (³¹ P-NMR (CDCl₃): δ11.68ppm (P), 12.26 ppm (P'), ² J_(PP) =22.4 Hz).

From P,P,P'-trimethyl P'- (dibutylamido) methylenebisphosphonate (seeExample 1) P,P,P'-trimethyl P- (dibutylamido)(dichloromethylene)bisphosphonate (³¹ P-NMR (CDCl₃): δ11.88 ppm (P),16.78 ppm (P'), 21.3 Hz).

From P'-ethyl P,P-dimethyl P'-(dioctylamido) methylenebisphosphonate(see Example 1) P'-ethyl P,P-dimethyl P'(dioctylamido)(dichloromethylene) bisphosphonate (³ 1 P-NMR (CDCl₃): δ11.93 ppm (P),15.15 ppm (P'), ² J_(PP) =22.1 Hz)

From P'-ethyl P,P-dimethyl P'-(benzylmethylamido)methylenebisphosphonate(see Example 1) P'-ethyl P,P-dimethyl P'-(benzylmethylamido)(dichloromethylene) bisphosphonate (³¹ P-NMR (CDCl₃): δ11.70 ppm. (P),15.01 ppm (P'), ² J_(PP) =23.0 Hz) .

From P'-ethyl P,P-dimethyl P'-(methylamido) methylenebisphosphonate (seeExample 9) P'-ethyl P,P-dimethyl P'(methylamido) (dichloromethylene)bisphosphonate (³¹ P-NMR (CDCl₃): δ13.26 ppm (P), 10.75 ppm (P), ²J_(PP) =23.0 Hz)

From P,P,P'-trimethyl P'-(butylamido)methylenebisphosphonateP,P,P'-trimethyl P'-(butylamido)(dichloromethylene)bisphosphonate.

From P,P,P'-trimethyl P'-piperidinomethylenebisphosphonate (seeExample 1) P,P,P'-trimethyl P'-piperidino(dichloromethylene)bisphosphonate.

From P,P,P'-triethyl P'-(diallylamido)methylenebisphosphonate (seeExample 1) P,P,P'-triethylP'-diallylamido(dichloromethylene)bisphosphonate.

EXAMPLE 5 (Dichloromethylene)bisphosphonic acid tetrakis (diethylamide)

Into 10.0 g (0.04 moles) of methylenebisphosphonic acid tetrachloride(prepared from tetraisopropylmethylenebisphosphonate and phosphoruspentachloride) in 60 ml of anhydrous toluene 23.4 g (0.32 moles) ofdiethylamine is added at <50° C. within appr. 30 min in 40 ml ofanhydrous toluene, whereafter the mixture is stirred for 1 hour at appr.50° C. and the mixture is cooled and filtered. The filtrate isevaporated under vacuum, whereby appr. 12.6 g (80% of theor.) ofmethylenebisphosphonic acid tetrakis(diethylamide) is obtained (³¹ P-NMR(CDCl₃): δ27.78 ppm) as a light yellow oil at a concentration of >85%.

The evaporation residue (8.0 g=0.02 moles) is chlorinated as has beendescribed in the Example 1 (stirring for 72 h at room temperature),whereby appr. 7.5 g (80% of theor. ) of (dichloromethylene)bisphosphonicacid tetrakis(diethylamide) (³¹ P-NMR (CDCl₃): δ26.29 ppm) is obtainedas a light yellow oil, at a concentration of >90%.

I.a. the following methylene and (dichloromethylene)bisphosphonic acidtetrakisamides can be prepared in an analogous manner frommethylenebisphosphonic acid tetrachloride:

Tetrakis (dioctylamido) (dichloromethylene) bisphosphonate (³¹ P-NMR(CDCl₃): δ26.50 ppm) over tetrakis(dioctylamido)methylenebisphosphonate(³¹ P-NMR (CDCl₃): δ28.00 ppm) .

EXAMPLE 6 P'-Morpholino (dichloromethylene) bisphosphonic acid methylester and its dimorpholinium salt

18.5 g (0.05 moles) of P'-morpholino(dichloromethylene)bisphosphonicacid P'-ethyl P,P-dimethyl ester (see Example 4) in 70 ml of piperidineis mixed for 20 min at appr. 100° C. and the mixture is evaporated undervacuum. The residue is stirred into anhydrous ether and the precipitateseparated by filtering and is washed with ether and dried to constantweight. The yield is appr. 20 g (80% of theor.) of colourlesscrystalline P'-morpholino(dichloromethylene)bisphosphonic acid P-methylester dipiperidinium salt (³¹ P-NMR (D₂ O): δ0.82 ppm (P), 9.70 ppm(P'), ² J_(PP) =15.4 Hz) at a concentration of >97% and wherefrom thecorresponding free bisphosphonic acid (³¹ P-NMR (CDCl₃): ) can beliberated with acid treatment.

I.a. the following symmetrical (dichloromethylene)bisphosphonic acidester amides can be prepared in an analogous manner:

From P,P,P'-trimethyl P'-(diethylamido)(dichloromethylene)bisphosphonate (see Example 4) P-methylP'-(diethylamido) (dichloromethylene) bisphosphonate (dimorpholiniumsalt, ³¹ P-NMR (D₂ O): δ11.10 ppm (P), 12.76 ppm (P') ² J_(PP) =15.3Hz).

From P,P,P'-trimethyl P'-(dibutylamido)(dichloromethylene)bisphosphonate (see Example 4) P-methylP'-(dibutylamido) (dichloromethylene-) bisphosphonate (disodium salt, ³¹P-NMR (D₂ O): δ11.16 ppm (P), 12.88 ppm (P') ² J_(PP) =16.2 Hz).

From P,P,P'-trimethyl P'-piperidino(dichloromethylene)bisphosphonate(see Example 4) P-methyl P'-piperidino(dichloromethylene)bisphosphonate(dipiperidinium salt, (³¹ P-NMR (D₂ O): δ10.90 (P), 10.41 (P'), ² J_(PP)=15.3 Hz)

From P,P,P'-triethyl P'-(diallylamido) (dichloromethylene)bisphosphonate (see Example 4) P-ethyl P'-(diallyl) (dichloromethylene)bisphosphonate (disodium salt, ³¹ P-NMR (D₂ O): δ9.98 ppm (P), 12.48 ppm(P') ² J_(PP) =15.6 Hz)

From P,P,P'-trimethyl P'-(phenylamido) (dichloromethylene)bisphosphonate (see Example ) P-methylP'-(phenylamido)(dichloromethylene) bisphosphonate (dianilinium salt, ³¹P-NMR (D₂ O): δ10.25 ppm (P), 6.60 ppm (P'), (² J_(PP) =17.3 Hz).

From P,P,P'-trimethyl P'-(phenylisopropylamido)(dichloromethylene)bisphosphonate (see Example ) P-methylP'-(phenylisopropylamido) (dichloromethylene)bisphosphonate (bis(N-isopropylanilinium salt), ³¹ P-NMR (D₂ O): δ10.48 ppm (P), 6.74 ppm(P'), ² J_(PP) =17.3 Hz

From P'-ethyl P,P-dimethyl P'-(benzylmethylamido)(dichloromethylene)bisphosphonate (see Example 4) P-methylP'(benzylmethylamido) (dichloromethylene) bisphosphonate (dipiperidiniumsalt, ³¹ P-NMR (D₂ O): δ10.86 ppm (P), 12.29 ppm (P'), ² J_(PP) =15.4Hz)

From P,P,P'-trimethyl P'-(butylamido) (dichloromethylene)bisphosphonate(see Example ) P-methyl P'-(butylamido)(dichloromethylene)bisphosphonate(³¹ P-NMR (D₂ O): δ8.15 ppm (P), 9.30 ppm (P') ² J_(PP) =20.2 Hz)

From P'-ethyl P-methyl P,P'-bis (diethylamido) (dichloromethylene)bisphosphonate (see Example 1) P,P'-bis(diethylamido)(dichloromethylene) bisphosphonate (disodium salt, ³¹ P-NMR (D₂ O):δ13.94 ppm). (Alternative preparation: see Example 1).

EXAMPLE 7 (Dichloromethylene) bisphosphonic acid P'-isopropyl esterP'-diethylamide and its disodium salt

7.4 g (0.02 moles) of (dichloromethylene)bisphosphonic acid P'-isopropylP,P-dimethyl ester P'-diethylamide (see Example 4) is dissolved in 120ml of anhydrous CH₃ CN and while stirring and cooling 5.6 ml (0.04moles) of anhydrous triethylamine as well as 20.3 ml (0.16 moles) ofchlorotrimethylsilane is added. The mixture is stirred under reflux for5 h and evaporated under vacuum, whereby appr. 9.7 g (100% of theor.) ofalmost colourless oily (dichloromethylene)bisphosphonic acidP'-isopropyl P,P-bis(trimethylsilyl) ester P'-diethylamide (³¹ P-NMR(CDCl₃): δ-8.92 ppm (P), 14.51 (P'), ² J_(PP) =23.7 Hz) is obtained.

The evaporation residue is mixed for 15 rain in 100 ml of anhydrousmethanol and the mixture is evaporated under vacuum. The yield is appr.6.1 g (90% of theor. ) of almost colourless crystalline(dichloromethylene) bisphosphonic acid P'-isopropyl esterP'-diethylamide (³¹ P-NMR (CDCl₃): δ8.37 ppm (P), 15.42 ppm (P'), ²J_(PP) =23.0 Hz) at a concentration of >97% and which with sodiumhydroxide treatment can be-converted to the corresponding disodium salt(³¹ P-NMR (D₂ O): δ7.93 ppm (P), 21.89 ppm (P'), ² J_(PP) =15.7 Hz ).

I.a. the following unsymmetrical (dichloromethylene)bisphosphonic acidester amides can be prepared in an analogous manner:

From P'-ethyl P,P-dimethylP'-(benzylmethylamido)(dichloromethylene)bisphosphonate over P'-ethylP,P-bis(trimethylsilyl)P'-(benzylmethylamido)(dichloromethylene)bisphosphonate P'-ethylP'-(benzylmethylamido)(dichloromethylene)bisphosphonate which may befurther converted to the corresponding disodium salt (³¹ P-NMR (D₂ O):δ7.63 ppm (P), 23.86 ppm (P'), ² J_(PP) =15.3 Hz).

EXAMPLE 8P,P-Bis(diethylaimido)P'-methyl(dichloromethylene)bisphosphonic acid andits tributylammonium salt

7.66 g (0.02 moles) of P,P-bis(diethylamido) P',P'-dimethyl(dichloromethylene) bisphosphonate (see Example 1) and 3.71 g (0.02moles) of anhydrous tributylamine are dissolved in 20 ml of anhydrouschloroform. The solution is stirred under reflux for 4 h and the solventevaporated under vacuum, whereby appr. 11.1 g (98% of theor. ) ofP,P-bis (diethylamido) P'-methyl (dichloromethylene) bisphosphonic acidmethyltributylammonium salt is obtained as a pale stiff yellow oil [³¹P-NMR (CDCl₃): δ27.88 ppm (P), 6.17 ppm (P'), ² J_(PP) =17.2 Hz, ³J_(PP) =10.2 Hz, ³ J_(PH) =9.0 Hz] at a concentration of 95% and fromwhich the corresponding acid may be liberated with acid treatment.

EXAMPLE 9 (Dichloromethylene)bisphosphonic acid P'-ethyl P-methyl esterP'-benzylmethylamide and its tributylammonium salt

4.40 g (0.01 moles) of (dichloromethylene) bisphosphonic acid P'-ethylP,P-dimethyl ester P'-benzylmethylamide (see Example 4) is dissolved in20 ml of anhydrous chloroform and 1.85 g (0.01 moles) of tributylamineis added and stirred under reflux for 4 h (the progress of the reactionis followed with NMR) and evaporated under vacuum. The yield is appr.5.8 g (100% of theor. ) of oily (dichloromethylene) bisphosphonic acidP'-ethyl P-methyl ester P'benzylmethylamide tributylmethylammonium salt(³¹ P-NMR (CDCl₃): δ4.94 ppm (P), 18.77 ppm (P'), ² J_(PP) =17.9 Hz) ata concentration of >97.% and which can be converted to the correspondingacid with acid treatment.

I.a. the following unsymmetrical (dichloromethylene)bisphosphonic acidester amides can be prepared in an analogous manner.

From P'-isopropyl P,P-dimethyl P'-(diethylamido)(dichloromethylene)bisphosphonate (see Example 4) the P'-isopropylP-methyl (diethylamido) (dichloromethylene) bisphosphonatetributylmethylammonium salt (free acid, ³¹ P-NMR (CDCl₃): δ8.53 ppm (P),15.18 ppm (P'), ² J_(PP) =21.1 Hz).

EXAMPLE 10 (Dichloromethylene)bisphosphonic acid (mono)methylamide andits trisodium salt

1.68 g (0.005 moles) of methylenebisphosphonic acid P'-ethylP,P-dimethyl ester P'-benzylmethylamide (see Example is dissolved in 16ml of acetic acid and 340 mg of 10% Pd/C is added. The mixture ishydrogenated at room temperature for 2.5 h and the catalyst is removedby filtration. To the filtrate fresh catalyst is added and hydrogenationis continued for 3 h. An additional 340 mg of fresh catalyst and 5 dropsof water are added and hydrogenated for 18 h. The mixture is filteredand the filtrate evaporated under vacuum, whereby appr. 0.75 g (60% oftheor.) of methylenebisphosphonic acid P'-ethyl P,P-dimethyl esterP'-methylamide (³¹ P-NMR (CDCl₃): δ24.73 ppm (P), 26.99 (p,) ² J_(PP)=5.5 Hz) is obtained at a concentration of >90%. The obtainedevaporation residue is chlorinated to form(dichloromethylene)bisphosphonic acid P'-ethyl P,P-dimethyl esterP'-(mono)methylamide (³¹ P-NMR (CDCl₃): δ10.75 ppm (P), 13.26 (P'),.sup. 2 J_(PP) =23.0 Hz) according to the process of step 2 of Example1, whereafter the P,P,P'-ester groups are hydrolysed over(dichloromethylene) bisphosphonic acid P,P,P'-tri(trimethylsilyl)esterP'-(mono)methylamide to (dichloromethylene)bisphosphonic acid(mono)methylamide according to the process of Example 1. By treating anacetone solution of the product with three equivalents of a 5N NaOHsolution, the corresponding trisodium salt is obtained as a colourlesscrystalline product.

EXAMPLE 11 (Chloromethylene)bisphosphonic acid P'-ethyl P,P-dimethylester P'-benzylmethylamide

2.0 g (0.005 moles) of dichloromethylenebisphosphonic acid P'-ethylP,P'-dimethyl ester P'-benzylmethylamide (see Example 4) in 20 ml ofethanol is added dropwise at 0° C. to a solution containing 2.4 g of Na₂SO₃ in 40 ml of water. After the addition the mixture is stirred for 40min (the progress of the reaction is followed with NMR). When thereaction has ceased, the mixture is extracted with CHCl₃ and the extractwashed with water, dried (Na₂ SO₄) and filtered. The filtrate isevaporated under vacuum, whereby appr. 1.5 g (80% of theor.) of(chloromethylene)bisphosphonic acid P'-ethyl P,P-dimethyl esterP'-benzylmethylamide is obtained (³¹ P-NMR (CDCl₃): δ17.51/17.20 ppm(P), 19.91/19.52 ppm (P'), ² J_(PP) =6.7/10.5 Hz diastereomer pair) asan almost colourless oil at a concentration of >90%.

I.a. the following symmetrical and unsymmetrical(chloromethylene)bisphosphonic acid ester amides can be prepared inanalogous manner:

From P,P,P'-trimethyl P'-(diethylamido) (dichloromethylene)bisphosphonate (see Example 4) P,P,P',-trimethyl P'-(diethylamido)(chloromethylene) bisphosphonate.

From P,P-dimethyl P', P'-bis (diethylamido)(dichloromethylene)bisphosphonate (see Example 1) P,P-dimethylP',P'-bis(diethylamido) (chloromethylene) bisphosphonate.

EXAMPLE 12 (Dichloromethylene) bisphosphonic acidP,P'-bis(tertbutyldiphenylsilyl) P-methylester P'-dibutylamide,(Dichloromethylene) bisphosphonic acid P,P'-bis(tertbutyldiphenylsilyl)P-trimethylsilylester P'-dibutylamide and(Dichloromethylene)bisphosphonic acid P,P'-bis(tertbutyldiphenylsilyl)P'-dibutylamide

1.85 (0.005 moles) of (dichloromethylene)bisphosphonic acid P-methylester P'-dibutylamide (see Example 6) and 4.12 g (0.015 moles) oftert-butyldiphenylsilyl chloride in 30 ml of anhydrous CH₃ CN arestirred for 3 h under reflux and the solvent is evaporated under vacuum.The yield is about 4.0 g (100% of theor.) of(dichloromethylene)bisphosphonic acid P,P'-bis(tert-butyldiphenylsilyl)P-methyl ester P'-dibutyl amide (³¹ P-NMR (CDCl₃): δ2.34/2.29 ppm (P),5.20/4.61 ppm (P'), ² J_(PP) =36.8/27.9 Hz, diasteromer pair) at aconcentration of >85%.

1.64 g (0. 002 moles) of (dichloromethylene) bisphosphonic acid P,P'-bis(tert-butyldiphenylsilyl) P-methyl ester P'-dibutyl amide is dissolvedin 15 ml of anhydrous CH₃ CN and 240 mg (0.0029 moles) ofchlorotrimethylsilane and 330 mg (0.0022 moles) of NaI are added and themixture is stirred for 1 h at room temperature and filtered. Thefiltrate is evaporated under vacuum, whereby appr. 1.7 g (95% of theor.) of (dichloromethylene) bisphosphonic acidP,P'-bis(tert-butyldiphenylsilyl) P-trimethylsilyl ester P'-dibutylamide is obtained (³¹ P-NMR (CDCl₃): δ-7.17/-7.73 ppm (P), 7.46/7.44 ppm² J_(PP) =28.9/31.3 Hz) as a brownish-yellow solid residue at aconcentration of >80%.

The evaporation residue is stirred for 15 min in 10 ml of anhydrous CH₃OH and the solution is evaporated under vacuum. The residue is stirredin 20 ml of anhydrous ether and the mixture filtered. The filtrate isevaporated under vacuum, whereby appr. 1.2 g (95% of theor.) of(dichloromethylene) bisphosphonic acid P,P'-bis(tert-butyldiphenylsilyl)P'-dibutyl amide is obtained (³¹ P-NMR (CDCl₃): δ0.27/-2.13 ppm (P),8.45/7.37 ppm (P') ² J_(PP) =23.7/32.3 Hz, diastereomer pair) as a paleyellow solid residue at a concentration of >88%.

EXAMPLE 13 (Dibromomethylene)bisphosphonic acid P-ethyl esterP,-P',P'-tris(diethylamide), (Bromomethylene)bisphosphonic acid P-ethylester P,P',P'tris(diethylamide) and (Bromochloromethylene)bisphosphonicacid P-ethyl ester P,P'P'-tris(diethylamide)

Into a sodium hypobromite solution which has been prepared by adding 8.4g of bromine into 4.6 g NaOH in 50 ml of water, 7.4 g (0.02 moles) ofmethylenebisphosphonic acid P-ethyl ester P,P'P'-tris(diethylamide), towhich has been added 50 ml of toluene and 5.0 g ofbenzyltriethylammonium chloride, is added while stirring (see Example 1)during appr. 10 min, whereafter stirring is continued for 24 h >40° C.The mixture is extracted with CH₂ Cl₂ and the extract is washed withwater and dried (Na₂ SO₄) and filtered. The filtrate is evaporated undervacuum, whereby appr. 5.8 g (55% of theor.) of(dibromomethylene)bisphosphonic acid P-ethyl esterP,P',P'-tris(diethylamide) (³¹ P-NMR (CDCl₃): δ16.95 ppm (P), 25.01 ppm(P'), ² J_(PP) =16.6 Hz) is obtained at a concentration of >90%.

In the corresponding manner P'-ethyl P,P-dimethylP'-(benzylmethylamido)methylenebisphosphonate P'-ethyl P,P-dimethylP'-(benzylmethylamido)(dibromomethylene)bisphosphonate (³¹ P-NMR(CDCl₃): δ11.95 ppm (P), 14.54 ppm (P'), ² _(PP) =18.1 Hz) can beprepared.

To 4.9 g (0.01 moles;) of (dibromomethylene) bisphosphonic acid P'-ethylP,P-dimethyl ester P'-benzylmethylamide (see above) in 70 ml of abs.ethanol 2.5 g of SnCl₂ ×H₂ O in 100 ml of water is added while stirringat 0° C., whereafter the stirring is continued for 15 min and themixture extracted with CHCl₃. The extract is dried (Na₂ SO₄) andfiltered and the filtrate evaporated under vacuum, whereby appr. 2.9 g(70% of theor. ) of (bromomethylene) bisphosphonic acid P'-ethylP,P-dimethyl ester P'-benzylmethyl amide is obtained (³¹ P-NMR (CDCl₃):δ17.29/17.21 ppm (P), 19.76/19.21 (P'), ² J_(PP) =4.5/10.5 Hz,diastereomer pair) at a concentration of >90%.

In the same manner one can from P-ethyl P,P',P'-tris(diethylamido)(dibromomethylene) bisphosphonate prepare P-ethyl P,P', P'-tris(diethylamido) (bromomethylene) bisphosphonate (³¹ P-NMR (CDCl₃):δ6.22.79/21.87 ppm (P), 25.37/24.71 ppm (P'), ² J_(PP) =2.7/10.1 Hzdiastereomer pair).

4.5 g (0.01 moles) of (bromomethylene)bisphosphonic acid P-ethyl esterP,P',P'-tris(diethylamide) is mixed into 50 ml of toluene, to which 3.0g of benzyltriethylammonium chloride has been added. The mixture isheated to 40°-50° C. and 70 ml of a 10% NaOCl-solution is added. Themixture is stirred intensively for 24 h at 40°-50° C. whereafter theorganic phase is separated and the aqueous phase is extracted with 2×50ml of toluene. The combined toluene phases are washed with 2×10 ml of asaturated NaCl-solution and dried (Na₂ SO₄) and filtered. The filtrateis evaporated under vacuum whereby appr. 3.4 g (70% of theor. ) of(bromochloromethylene) bisphosphonic acid P-ethyl esterP,P',P'-tris(diethylamide) is obtained (³¹ P-NMR (CDCl₃): δ17.00/17.23ppm (P), 25.72/25.32 ppm (P'), ² J_(PP) =19.2/18.1 Hz diastereomerpair).

We claim:
 1. Methylenebisphosphonic acid ester derivatives having thegeneral formula I ##STR10## in which formula W¹, W², W³ and W⁴ areindependently the group OR¹ or the group NR² R³ wherein R¹, R² and R³independently are hydrogen or straight or branched C₁ -C₈ alkyl, benzylor phenyl, or the groups R² and R³ form together with the adjacentnitrogen atom a piperidino or morpholino ring, provided that in theformula I at least one of the groups W¹, W², W³ and W⁴ is hydroxy and atleast one of the groups W¹, W², W³ and W⁴ is the amino group NR² R³,Q¹is hydrogen or chlorine, and Q² is chlorine, including thestereoisomers, such as the geometrical isomers and the optically activeisomers, of the compounds, as well as the pharmacologically acceptablesalts of the compounds.
 2. Methylenebisphosphonic acid derivativeselected from the group consisting of:(dichloromethylene)bisphosphonicacid P,P,P'-tris(diethyl amide), (dichloromethylene)bisphosphonic acidP-monoisopropyl ester P-mono(diethylamide),(dichloromethylene)bisphosphonic acid P,P-bis(diethylamide),(dichloromethylene)bisphosphonic acid mono(diethylamide),(dichloromethylene) bisphosphonic acid mono(phenyl-N-methyl amide),(dichloromethylene) bisphosphonic acid mono(benzylamide), and(dichloromethylene) bisphosphonic acid P,P'-bis(diethylamide), includingthe stereoisomers, such as the geometrical isomers and the opticallyactive isomers, of the compounds, as well as the pharmacologicallyacceptable salts of the compounds.
 3. Pharmaceutical composition,characterized in that it contains as the active agent a compound of theformula I according to the claim
 1. 4. The composition according to theclaim 3 wherein the active agent is selected from the group consistingof:(dichloromethylene)bisphosphonic acid P,P,P'-tris(diethyl amide),(dichloromethylene)bisphosphonic acid P-monoisopropyl ester P-mono(diethylamide), (dichloromethylene)bisphosphonic acidP,P-bis(diethylamide) (dichloromethylene)bisphosphonic acidmono(diethylamide), (dichloromethylene)bisphosphonic acidmono(phenyl-N-methyl amide), (dichloromethylene)bisphosphonic acid mono(benzylamide), and (dichloromethylene)bisphosphonic acidP,P'-bis(diethylamide).
 5. A method of treating a physiological disorderrelating to the metabolism of calcium or other divalent metals, or to(pyro)phosphate functions, by administering to a patient apharmacological composition characterized in that it has as an activeagent a compound having the formula I according to claim
 1. 6. Themethod according to the claim 5, wherein the active agent is selectedfrom the group consisting of:(dichloromethylene)bisphosphonic acidP,P,P'-tris(diethyl amide), (dichloromethylene)bisphosphonic acidP-monoisopropyl ester P-mono(diethylamide),(dichloromethylene)bisphosphonic acid P,P-bis(diethylamide),(dichloromethylene)bisphosphonic acid mono(diethylamide)(dichloromethylene)bisphosphonic acid mono(phenyl-N-methyl amide),(dichloromethylene) bisphosphonic acid mono (benzylamide), and(dichloromethylene) bisphosphonic acid P,P'-bis(diethylamide).